治疗帕金森病的药物课件

1MotorsystemsII:ThebasalgangliaandDrugsusedforthetreatmentofParkinson’sdiseaseZhangBin（张斌）InstituteofPharmacologySchoolofMedicineShandongUniversity1MotorsystemsII:Thebasalg治疗帕金森病的药物课件1.ComponentsofBasalGanglia3neostriatumstriatum(paleostriatum)1.ComponentsofBasalGanglia1.CaudateNucleus(尾状核）2.Putamen

(壳核,豆状核壳）3.GlobusPallidus(GP)

（苍白球，旧纹状体）4.SubstantiaNigra(SN)（黑质）

ParsCompacta

(p.c.)

(致密部）

ParsReticulata(p.r.)

（网状部）5.SubthalamicNucleus(STN)(丘脑底核）4新纹状体新纹状体是基底节的核心，许多神经传入进来，也会发出神经纤维到其他部位，构成回路调控躯体运动1.CaudateNucleus(尾状核）4新纹状体新2.

Mediumspinyneuroninstriatum

(MSN,中型多棘神经元)

1)MSN

isthemainefferentneuronsinneostriatum2)MSN（Dendrites）接受的afferent神经:Glu

neuronsincortexDA

neuronsinSNcAch

neuronsinstriatumGABA

neurons

instriatum

3)MSNaxonscomposeefferentsystem,withGABAastheneurotransmitter

52.Mediumspinyneuroninstri4)TwotypesofDAreceptorsonMSN:D1

andD2-R

D1-R:enhancedirectpathway→Gpi(苍白球内侧部)D2-R:inhibitindirectpathway→GPe(苍白球外侧部)64)TwotypesofDAreceptorso73.CircuitrelatedwithBasalganglia’sfunctionincontrolofmovement73.CircuitrelatedwithBasal81)directpathway(直接通路):当新纹状体活动↑→皮层运动前区活动↑2)indirectpathway

(间接通路):当新纹状体活动↑→皮层运动前区活动↓。此通路部分抵消直接通路对皮层的兴奋作用3)Substantianigra-Neostriatumpathway(黑质-新纹状体通路):此通路对上述两通路起调控作用DA通过D1受体增强直接通路，通过D2受体抑制间接通路81)directpathway(直接通路):当新94.Diseasesrelatedwithdysfunction

ofBasalgangliaHuntington’sdisease(Chorea)运动过多，肌张力降低Parkinsondisease运动减少，肌张力增高94.Diseasesrelatedwithdysf101011Parkinson’sDisease11Parkinson’sDisease12CNSdegenerativediseaseAlzheimer’sdisease(AD,阿尔茨海默病)Parkinson’sdisease(PD,帕金森病)Huntingtondisease(HD,亨廷顿病)Amyotrophiclateralsclerosis(ALS,

肌萎缩侧索硬化症)12CNSdegenerativediseaseAMuhammadAliinAlantaOlympicParkinson’sDiseaseKatharineHepburn

Michael·J·FoxMuhammadAliinAlantaOlympic14Firstdescribedin1817byanEnglishphysician,JamesParkinson,in“AnEssayontheShakingPalsy.”

“paralysisagitans”(震颤麻痹)Parkinson’sDisease

-History

JamesC.Parkinson14Firstdescribedin1817bya15ThefamousFrenchneurologist,Charcot,furtherdescribedthesyndromein1868

(rigidity)named”Parkinsondisease”.1919:确定病变部位主要在黑质1960:发现与黑质纹状体中DA含量显著降低有关世界帕金森病日每年的4月11日——15ThefamousFrenchneurologis16

Parkinson’sDisease-

Symptoms1.Restingtremor(静止震颤)2.Bradykinesia(运动迟缓)3.Rigidity(肌肉强直)Cogwheelphenomenon(Leadpipephenomenon)4.Ataxia(共济失调)颤，慢，硬，共济失调16Parkinson’sDisease-Sympt175.OthersAbnormalityofpostureandgaitHandwritingMemoryimpairment,confusion(精神混乱),disorientationCognitivedeficitsDepression175.Others1818PresymptomaticphaseOnsetSleepOlfactory*MoodAutonomicsystemDiagnosisEarlynonmotorsymptomsSpecificsymptomsMotorPDsymptoms

DopaminergicneuronlossinPD%Remaining

DopaminergicNeuronsTime(years)NonmotorAdaptedimagereprintedfromNeurotherapeutics,Vol.6,HalperinI,MorelliM,KorczynAD,YoudimMB,MandelSA.BiomarkersforevaluationofclinicalefficacyofmultipotentialneuroprotectivedrugsforAlzheimer'sandParkinson'sdiseases,pages128-140,Copyright2009,withpermissionfromElsevier.*OlfactorydysfunctionmaypredateclinicalPDbyatleast4years.Halperinetal.Neurotherapeutics.2009;6:128-140.Lang.Neurology.2007;68:948-952.Rossetal.AnnNeurol.2008;63:167-173.PresymptomaticphaseOnsetSleep20PD

-

EpidemiologyThesecondmostcommonneurodegenerativedisorderafterAD.Increasewithagepopulation>65yearsold:1%meanageatonset:60yearsold85%ofpatientsareover65yearsold20PD-EpidemiologyThesecond21PD

-

EtiologyUnknownIncreasingage(rareinthose<50;earlyoryoungonset)MoreoftentooccurinfamilieswithrelativeswithPDEnvironmentalfactors(pesticides,ruralresidence)Headtrauma,InfectionCaffeineandsmokinghavebeenfoundtobeprotective21PD-EtiologyUnknown22RiskofParkinson’sDiseaseIncreasedriskAgeHighBodyMassIndexMalegenderFamilyhistoryDepressionEnvironmentfactorsrurallivingwell-waterdrinkingwelding（焊接）headinjuryDecreasedriskCaffeineintakeSmokingcigarettesAnti-oxidantsindiet

(如类黄酮)22RiskofParkinson’sDiseaseI23

PD-Classification1.PrimaryPD：unknown2.Secondary:ParkinsonismCerebralarteriosclerosis

Encephalitis(脑炎)Drugpoison:氰化物、利舍平、吩噻嗪类抗精神病药等Chemicals:Mn2+、除草剂、杀虫剂等23PD-Classification1.Primar241.Dopamine(DA)theory

PD-

Pathophysiology(1)DAneuronaldegenerationinsubstantianigra

reducedorlackofdopamine

inthestriatum

↓functionofDAinnigro-striatalDApathway

↑thefunctionofAch

musculartension241.Dopamine(DA)theoryPD-25NormalPDsubstantianigra正常人中脑有一条狭长的黑色素沉着部位，是正常数量的黑质神经元聚集的部位。而在帕金森病人中脑的相应部位则颜色浅淡，是黑质神经元减少的缘故.25NormalPDsubstantianigra正常人中26DopaminetheoryAch黑质纹状体DADA(—)(＋)调节运动功能脊髓前角运动神经元GABA26DopaminetheoryAch黑质纹状体DADA(27DA氧化代谢H2O2、O2-·

·OH

Fe2+促进神经膜类脂氧化破坏DA神经细胞膜功能

ComplexⅠ

抗氧化物（谷胱甘肽）黑质2.Oxidativestress-freeradicaltheory

PD-

Pathophysiology(2)抗氧化治疗(MAO-BI,VitE):早期PD首选治疗方案。尽量延缓使用L-DOPA。是PD治疗较大的进展和传统观念的转变27DA氧化代谢H2O2、O2-··OHFe2+促进28PD-AnimalmodelMPTP6-OHDARotenoneParaquat28PD-AnimalmodelMPTP29PD-TreatmentNocureforPDDopaminergicmedicationNon-dopaminergicmedicationOtherstrategiesSurgicalintervention(外科手术)Regularexercise(定期训练)29PD-TreatmentNocureforPD30AntiparkinsonismdrugsDAAchDopaminomimeticDrugsCentralAnticholinergicDrugs30AntiparkinsonismdrugsDAAchD31AADCTH:酪氨酸羟化酶THAADC:L-芳香族氨基酸脱羧酶31AADCTH:酪氨酸羟化酶THAADC:L-芳香族氨基酸32

ⅠDopaminomimeticDrugs

1.

PrecursorofDA

2.SynergeticagentsofL-dopa

(左旋多巴的增效药）

3.DAreceptoragonists

4.DrugsenhancingDArelease32ⅠDopaminomimeticDrug331.

PrecursorofDA

levodopa（L-dopa,左旋多巴）LevodopaDopamine331.PrecursorofDAlevodop34【Pharmacologicalactionsandmechanism】PenetrateBBBintothebrainDecarboxylated

(脱羧)

byAADCtoDASupplyDAtostriatum

34【Pharmacologicalactionsan35【Clinicaluse】widelyusedforalmostalltypesofPDpatients

1.Parkinson’sdisease:symptomatictreatment(1)earlystage:goodandstableeffect80%canbesignificantlyimproved,ofwhich20%recoverdtothenormalstate(2)laterstage:effectgraduallydecreased,littleeffect

after3-5years用药初期和用药后期疗效差距很大35【Clinicaluse】widelyusedf36Characteristics:

(1)havegoodeffectonmildandyoungerpatients,lesseffectonsevereandelderlypatients(2)moreeffectiveformuscularrigidityandakinesia(运动不能),lesseffectiveforrestingtremor,difficulttoimprovedementia(3)slowonset,initialeffectivetimeis2-3w,1-6mtoEmax

(4)noteffectiveforParkinsonismcausedbyphenothiazinesantipsychoticdrugs(5)drugcombination:combinedwithperipheralAADCinhibitor,reducethedosageofL-DOPAby75%.Cabidopa(卡比多巴)orbenserazide(苄丝肼)36Characteristics:(1)haveg372.Hepaticcoma(肝昏迷):symptomatictreatmentfalseneurotransmittertheory

(伪递质学说）Levodopametabolizedtonoradrenaline

(NA)toreplacefalseneurotransmitter372.Hepaticcoma(肝昏迷):symp38食物中芳香族氨基酸脱羧酶酪胺和苯乙胺被肝中MAO清除肠菌肝功能血浓度脑组织羟化酶苯乙醇胺羟苯乙胺(鱆胺)神经传导障碍肝昏迷左旋多巴去甲肾上腺素改善神经传导脑内转变作为伪递质取代去甲肾上腺素肝功能正常38食物中芳香族氨基酸脱羧酶酪胺和苯乙胺被肝中MAO清除肠菌39【Pharmacokinetics】1.Absorptionoral,absorbedbysmallintestine,t1/21-3hBioavailabilityisaffectedbygastricemptying,gastricacidpH

(delayofemptyandlowPHcandecreasebioavailability)39【Pharmacokinetics】1402.DistributionandmetabolismLevodopaCOMTreuptakeMAOMAO:单胺氧化酶COMT:儿茶酚胺-O-甲基转移酶3.Elimination:kidney—AADCPeripheralCOMTDA402.Distributionandmetaboli41【Adversereactions】1.earlyreactions：(1)Gastrointestinaleffect:80%anorexia(厌食),nausea,vomitingtoleranceafterseveralweeks

domperidone(多潘立酮)外周D2-Rblocker(2)Cardiovasculareffects:orthostatichypotension30%arrhythmias41【Adversereactions】1.42

【Adversereactions】2.long-termreactions(1)Hyperkinesia(运动过多症,dyskinesia,运动障碍):50%(2-4m),90%(＞2years)

hand,feet,body—abnormalchoreoathetoidmovements(舞蹈手足徐动症)involuntarymovement(不随意运动)orofacial(triad)

:sucking,lickingthetongue,chewingDA-RblockeroverstimulationofDA-R42【Adversereactions】2.43(2)Fluctuationsinresponse

(症状波动):

on-offphenomena40%-80%(3-5years)(3)Psychicdisorders

Clozapine(氯氮平)：D4MAOIinhibitorDA-Ragonistivd,frequency

43(2)Fluctuationsinresponse44

【Druginteractions】VitB6:

coenzymeofAADC,

theactivityofAADCAntipsychoticdrugs:blockDA-RofNigro-striatalsystem,weakenL-DOPAfunction44【Druginteracti452.SynergeticagentsofL-dopa

(左旋多巴的增效药）AADC(芳香氨基酸脱羧酶)inhibitors

cabidopa,benserazide(苄丝肼)

(2)MAO-Binhibitors

selegiline(司来吉兰)(3)COMTinhibitors

nitecapone(硝替卡朋）452.SynergeticagentsofL-do46MetabolismofL-dopaL-DOPADAAADCCOMT3-OMDL-DOPA3-OMDDAAADCdegradationMAO-BCOMTreuptake(3-O-甲基多巴)BBBBrainPeripherycompeteCarrier46MetabolismofL-dopaL-DOPADAX47(1)AADCinhibitors(≠BBB)L-DOPADAAADCCOMT3-OMDL-DOPAcompeteCarrier3-OMDDAAADCdegradationMAO-BCOMTreuptake(3-O-甲基多巴)BBBBrainPeripheryX47(1)AADCinhibitors(≠BBB)L48Carbidopa(卡比多巴):

notpenetrateBBB,onlyinhibitperipheryAADC,

increaseL-dopaintothebrain,reducethedosageofL-dopaby75%Benserazide(苄丝肼):

similar

CompoundPreparationsSinemet(息宁，心宁美)Levodopa:Carbidopa(10:1)Madopar(美多巴)Levodopa:Benserazide(4:1)48Carbidopa(卡比多巴):Compoun49(2)MAO-Binhibitors(＝BBB)L-DOPADAAADCCOMT3-OMDL-DOPA3-OMDDAAADCXdegradationMAO-BCOMTreuptake(3-O-甲基多巴)BBBBrainPeripherycompeteCarrier49(2)MAO-Binhibitors(＝BBB)L50Selegiline(司来吉兰)

BBBpermeable,inhibitMAO-B:CNSreduceL-dopadoseand“on-offphenomena”

lowdose(＜10mg/d)—onlyinhibitMAO-B→DA↑highdose(＞10mg/d)—inhibitMAO-A,too→

hypertensivecrisis

antioxidanteffect50Selegiline(司来吉兰)BBBpermea5151治疗帕金森病的药物课件X53(3)COMTinhibitors(≠or＝

BBB)L-DOPADAAADCCOMT3-OMDL-DOPA3-OMDDAAADCXdegradationMAO-BCOMTreuptake(3-O-甲基多巴)BBBBrainPeripherycompeteCarrierX53(3)COMTinhibitors(≠or＝B54Periphery:CNS:DAdegradation↓→DAinCNS↑L-DOPAdegradation↓3-OMD(3-O-甲基多巴)↓carrieravailableforL-DOPA↑L-DOPAthatreachthebrain↑nitecapone(硝替卡朋):peripheryEntacapone(恩他卡朋):peripheryTocapone(托卡朋):peripheryandCNS54Periphery:L-DOPAdegradatio55Dopaminereceptorsfivemainsubtypes:D1~D5

D1-likereceptors:D1,D5D2-likereceptors:D2,D3,D43.DAreceptoragonistsNigro-striatalsystem:激活D1-likereceptor(D1,D5):兴奋激活D2-likereceptor(D2,D3):抑制55Dopaminereceptorsfivemain56Bromocriptine(溴隐亭):

D2agonism,D1partialantagonismPramipexole(普拉克索，森福罗):D2agonismRopinirole(罗平尼咯):D2agoni